Characterization of lymphoid tissue inducer cells and lymphoid tissue development in adult interleukin 7 transgenic mice

During embryogenesis, the development of secondary lymphoid organs (SLOs) such as lymph nodes (LNs) and Peyer’s patches (PPs) requires the cellular crosstalk between vascular cell adhesion molecule (VCAM)-1+ mesenchymal organizer cells and CD45+CD4+lin- lymphoid tissue inducer (LTi) cells. The cascade of events leading to functional SLOs is triggered by the activation of the lymphotoxin β receptor (LTβR) signalling pathway. LTi cells express the corresponding ligand lymphotoxin (LT) αβ, and other tumor necrosis factor super-family members, chemokine receptors, adhesion molecules and Interleukin 7 Receptor alpha (IL-7Rα), which contribute to the formation of SLOs. However, the precise mechanism of surface receptor engagement for lympho-organogenesis and LTi cell function was not fully understood. In addition, it remained unclear if LTi cells could persist in adult mice, and had a function in the adult immune system. In order to better understand the role of IL-7 in SLO development, we generated a double transgenic mouse model overexpressing IL-7 under the control of an ubiquitous promoter (termed H-IL-7). These mice developed additional ectopic LNs and PPs (1). Ectopic SLO development was strictly dependent on LTi cells. We further showed that the development of ectopic SLOs was mediated by an IL-7- driven increase in the survival of fetal LTi cells and its progenitors. CD4+lin- cells were found in significant numbers in all SLOs of adult H-IL-7 mice. This study was performed to characterize CD4+lin- cells in adult mice, and to identify their function. Adult CD4+lin- cells shared the phenotype with fetal LTi cells, including the expression of retinoic acid-related orphan receptor (ROR) γt. By transferring adult CD4+lin- cells into PP-deficient CXCR5-/- mice, we demonstrated their ability to generate lymphoid tissue. Thus, adult CD4+lin- cells were bona fide LTi cells. In order to test if adult LTi cells were present in normal wild type (WT) mice, and could respond to IL-7, we treated adult WT mice with IL-7/anti-IL-7 antibody (Ab) complexes. The pool of LTi cells was significantly increased in treated as compared to untreated mice demonstrating that adult LTi cells were responsive to IL-7. We further investigated the origin of adult LTi cells. We could show that the adult bone marrow (BM) could give rise to LTi cells, which was even more pronounced, when normal WT mice were treated with IL-7/anti-IL-7 Ab complex. BM cells were, however, far less efficient in generating LTi cells than fetal liver (FL) cells. It is well established that chronic inflammatory diseases in humans are often associated with a process termed "lymphoid neogenesis". Lymphoid neogenesis leads to the development of tertiary lymphoid organs (TLOs) in non-lymphoid organs. In several autoimmune diseases, a correlation between TLO development and IL-7 production has been reported, but experimental evidence for a causal role of IL-7 in TLO development was lacking. In adult H-IL-7 mice, we observed the development of TLOs in several non-lymphoid organs such as the salivary gland. Moreover, these TLOs were either diffuse or segregated in B and T cell areas, a hallmark of normal SLOs. LTi cells colonized the salivary gland before naive lymphocytes, but were not strictly required for TLO development. In contrast, the expression of LTα was essential for the organization of TLOs into segregated compartments. To test if local inflammation could trigger the development of TLOs in H-IL-7 mice, we infected mice s.c. with Leishmania major. At sites of infection but not in noninfected H-IL-7 mice, we found additional ectopic LNs. Moreover, the number of LTi cells was significantly increased in the draining LNs of both WT and H-IL-7 infected mice compared to non-infected. Altogether, these data show that the overexpression of IL-7 was able to induce lymphoid neogenesis at ecopic sites. In summary, this study shows that IL-7 is an important cytokine for the regulation of TLO development in adult mice. We have identified adult LTi cells, which infiltrate TLOs and may have a function in organizing the architecture of TLOs through activation of the LTβR signalling pathway

Paramedics in Switzerland: A Mature Profession.

This paper describes how the profession of paramedics has evolved in Switzerland and takes the perspective of public health. Ambulance drivers play an important role in the health system, not only as a response to emergencies, but also by working in an interprofessional and interdisciplinary manner in response to other public health needs, such as home care, triage, telemedicine and interhospital transfers. This pre-hospital system is rapidly evolving and relies on the work of paramedics

TATTOO-seq delineates spatial and cell type-specific regulatory programs in the developing limb

The coordinated differentiation of progenitor cells into specialized cell types and their spatial organization into distinct domains is central to embryogenesis. Here, we developed and applied an unbiased spatially resolved single-cell transcriptomics method to identify the genetic programs underlying the emergence of specialized cell types during mouse limb development and their spatial integration. We identify multiple transcription factors whose expression patterns are predominantly associated with cell type specification or spatial position, suggesting two parallel yet highly interconnected regulatory systems.We demonstrate that the embryonic limb undergoes a complex multiscale reorganization upon perturbation of one of its spatial organizing centers, including the loss of specific cell populations, alterations of preexisting cell states' molecular identities, and changes in their relative spatial distribution. Our study shows how multidimensional single-cell, spatially resolved molecular atlases can allow the deconvolution of spatial identity and cell fate and reveal the interconnected genetic networks that regulate organogenesis and its reorganization upon genetic alterations

RUNX1-dependent RAG1 deposition instigates human TCR-δ locus rearrangement

V(D)J recombination of TCR loci is regulated by chromatin accessibility to RAG1/2 proteins, rendering RAG1/2 targeting a potentially important regulator of lymphoid differentiation. We show that within the human TCR-α/δ locus

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

The original version of this article unfortunately contained a mistake